Background: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that can involve almost any organ and can range in severity from mild to life-threatening. In spite of significant improvements in survival of SLE patients over last 20 years, a significant portion of patients still develop progressive therapy-refractory disease that impairs organ function and overall survival. Moreover, although current immunosuppressive regimens have dramatically improved its prognosis they are not uniformly effective and are associated with significant toxicities. Elucidation of the pathogenesis of lupus is of paramount importance to improve the currently available therapeutic regimens. Production of pathogenic autoantibodies by B lymphocytes and formation of immune complexes are the hallmarks of the disease. Although absolute B lymphocyte numbers are low or normal in patients with SLE, they have an activated phenotype. Little is known, however about the role of different subsets of B cells and their relation to disease activity. Autoantibody production is antigen driven and depends on activated T cells. Recently it has been recognized that a subset of T cells the so-called regulatory T lymphocytes play an important role in the suppression of ongoing immune activation. It is conceivable that abnormalities in regulatory T cell may contribute to autoimmune diseases. Although the primary event in the initiation of autoimmunity is unknown, by the time SLE is clinically evident there is a self-perpetuating activation of autoreactive B- and T-cells in the lymphoid organs. Once activated, B cells can form memory cells; differentiate into auto-antibody forming plasma cells or plasmablasts; and present auto-antigen to T-cells, inducing proliferation of more activated T cells leading to amplification of this process. Interfering with this process by either blocking pro-inflammatory cytokines, such as IL-6, or by completely eradicating the abnormal immune system may lead to interruption of the autoimmune response and clinical benefit. Most manifestations of SLE are immune mediated. The mechanism of cognitive dysfunction is much less understood. Understanding the causes of cognitive abnormalities is very important since 30-60% of SLE patients suffer from some degree of cognitive dysfunction and cognitive dysfunction of long duration or with deterioration can have a significant impact on occupational functioning of SLE patients. Recently, it was demonstrated that a subset of anti-DNA antibodies cross-reacts with the human N-methyl-D-aspartate (NMDA) receptor and can cause excitotoxic death of neurons. NMDA receptors are important in memory function and learning, and thus such antibodies may mediate cognitive dysfunction in SLE. Objectives: 1. To evaluate the safety and to collect preliminary data about the efficacy of interleukin-6 blockade in patients with SLE. 2. To assess the relationship between cognitive dysfunction and anti-glutaminergic autoantibodies in SLE 3. To assess the curative potential of intensified immunoablation followed by stem cell transplantation in severe SLE. 4.To analyze B lymphocyte subsets and identify subsets that may be related to changes in disease activity 5. To analyze the function of regulatory T lymphocytes. Results: 1. We started a Phase I, dose escalating open label study with an anti-IL6 receptor monoclonal antibody in patients with SLE. 2. We started an observational study of cognitive function in patients with SLE. Participants get detailed cognitive evaluation, MRI and MR spectroscopy of the brain and are tested for the presence of anti-glutaminergic autoantibodies and other potential biomarkers in the serum and CSF. 3. In close collaboration with the NCI, we established a protocol for intensive immunoablation followed by autologous stem cell transplantation in severe lupus. We use a novel conditioning treatment with fludarabine, cyclophosphamide and rituximab and address the curative potential of this approach. An important element of the protocol is the broad spectrum of associated laboratory studies addressing the mechanism of the regeneration of the immune system and the role of various subsets of immune cells in tolerance or autoimmunity. 4. B cell subsets in SLE. In collaboration with the Autoimmunity Branch, we characterized the abnormal B cell pattern of lupus patients. We identified B cell subsets that are not normally found in the peripheral blood some of which seem to correlate with disease activity. The functional characterization of these cells is in progress. 5. Regulatory T cells: our data indicate that Treg are abnormal in number, phenotype and function in patients with active SLE that could contribute to the pathogenesis of disease flares in these patients. Lay Summary: Systemic lupus erythematosus (SLE) is so called autoimmune disease, in which the body turns against itself producing antibodies directed to molecules found in body tissues (antigens). SLE can involve almost any organ and can range in severity from mild to life-threatening. Although current immunosuppressive regimens have dramatically improved its prognosis they are not uniformly effective and are associated with significant toxicities. Antibodies are produced by a certain type of immune cells called B lymphocytes. Although patients with active SLE usually have lower number of B lymphocytes in their blood they are more active then in healthy people. Interfering with this process by either blocking molecules that increase antibody production, such as interleukin-6, or by completely eradicating the abnormal immune system may lead to interruption of the autoimmune response and clinical benefit. We have started a treatment study blocking interleukin-6 with a man-made antibody for patients with mild-to-moderate lupus and established a study using bone marrow transplant for patients with severe lupus who have failed other treatments. We also started a study to find out more about the causes of problems with higher thinking and memory many lupus patients experience. We combine neurocognitive testing with sophisticated imaging and laboratory studies. Progress since last year 1. Anti-IL6R monoclonal antibody in SLE. We have almost completed treatment in the first dose group. 2. Neurocognitive dysfunction in SLE: we completed the study in over 30 patients of the 60 planned. 3. Intensified immunoablation followed by autologous stem cell transplant: We submitted a protocol to the IRB and FDA. The protocol has several novel features: it uses an induction regimen that has not been used in autoimmune diseases previously, has strictly defined inclusion, exclusion and response criteria and addresses the curative potential of this approach by comining the clinical studie with detailed mechanistic studies. External scientific reviewers considered the protocol to be innovative, timely and very important, that could only be done in the intramural NIH. 4. We studied the peripheral B lymphocytes of patients with active lupus nephritis and identified several subsets that are not found in the peripheral blood of healthy people, some of which correlate with disease activity. 5. Our data suggest that impaired regulatory T cell function in patients with active lupus. Goals for next year Continue the study with the anti-IL6 receptor monoclonal antibody and start enrollment into the autologous stem cell therapy program. We are considering to establish a new protocol with a B lymphocyte depleting monoclonal antibody in patients with active SLE. Continue to study the correlation between disease activity and B cell phenotypes. Define regulatory T cell abnormalities further. Start a study evaluating the role of immunoglobulin secreting cells in the kidney of patients with lupus nephritis.